小宮根 真弓

Psoriatic arthritis (PsA) is a chronic inflammatory disorder that affects approximately 20-30% of patients with psoriasis. PsA causes deformities and joint damage, impairing quality of life and causing long-term functional disability. Several recent studies demonstrated that early diagnosis and intervention for PsA prevents permanent invalidity. However, the clinical features of PsA vary and are shared with other differential diseases, such as reactive arthritis, osteoarthritis, and ankylosing spondylitis. The common and overlapping features among these diseases complicate the accurate early diagnosis and intervention of PsA. Therefore, this review focuses on the current knowledge of the diagnosis of early PsA and discusses the meaning of early intervention for early PsA.

BACKGROUND: IL-33 is a dual-functional molecule; it acts as a cytokine to enhance type 2 inflammation, and as a nuclear factor. The roles of nuclear IL-33 are not yet fully understood. OBJECTIVE: We aimed to investigate the role of IL-33 in normal human epidermal keratinocytes (NHEKs). METHODS: We utilized RNA interference to knock down cellular IL-33. RESULTS: The IL-33-knockdown (KD) cells showed decreased BrdU incorporation and decreasing tendency in RhoA activity and decreased ECT2 oncogene expression, compared to the controls. Supplementation of IL-33 expression utilizing adenovirus vector recovered the BrdU incorporation in IL-33-KD cells. Increased number of G2/M phase cells and binucleated cells were observed among the KD cells. Overtime observation revealed that IL-33-KD cells could not divide properly, formed binucleated cells, and were less motile than control cells. CONCLUSION: IL-33 KD in NHEKs affected the division and motility, probably by slightly decreasing the RhoA activity by attenuating ECT2 expression.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing COVID-19 pandemic has affected both daily life and medical care; therefore, the aim of this study was to analyze the use of biologics for inflammatory skin diseases during the COVID-19 pandemic in our hospital. The observation period was between 1 January 2020 and 23 February 2021. In this study, we enrolled 227 patients with psoriasis, six patients with palmoplantar pustulosis (PPP), 69 patients with atopic dermatitis (AD), and five patients with hidradenitis suppurativa (HS). Bioswitch was performed in 25 patients with psoriasis (11.0%). Biologics were discontinued in 14 patients with psoriasis (6.2%), 10 patients with AD (14.5%), and four patients with HS (80.0%); they were not discontinued in patients with PPP. The introduction of biologics was observed in 27 patients with psoriasis (11.9%), four patients with PPP (66.7%), 33 patients with AD (47.8%), and two patients with HS (40.0%). The use of telephone consultations was observed in four patients with psoriasis and two patients with AD. One patient, who received adalimumab for the treatment of psoriatic arthritis, suffered from COVID-19 and recovered after a mild course. In conclusion, we report our experience regarding the use of biologic drugs for inflammatory skin diseases. The use of biologics seemed safe for use amidst COVID-19 infection during the observation period; however, further observation on a larger number of patients is required to confirm the risks and benefits of biologic use in the COVID-19 era.

Apremilast is an orally available phosphodiesterase 4 inhibitor used for the treatment of moderate to severe psoriasis. The aims of this analysis were to develop a population pharmacokinetic (PPK) model of apremilast based on observed data from phase 1 studies combined with clinical trial data from subjects with moderate to severe psoriasis, and to develop exposure-response (E-R) models to determine whether Japanese subjects with moderate to severe psoriasis achieve response to apremilast treatment similar to that observed in non-Japanese, predominantly Caucasian subjects with moderate to severe psoriasis. The PPK model demonstrated that apremilast plasma concentrations and overall apparent clearance rate were comparable between the Japanese and Caucasian subgroups. The E-R analyses of ≥75% or ≥50% improvement from baseline in Psoriasis Area and Severity Index score and achievement of static Physician Global Assessment score of 0 (clear) or 1 (almost clear) at week 16 indicated that apremilast treatment in Japanese subjects approached the maximal effect with response rates comparable to those in predominantly Caucasian subjects. Overall, the analyses confirm that the approved apremilast 30 mg b.i.d. dose is appropriate for Japanese subjects with moderate to severe psoriasis, with an efficacy profile similar to that previously observed in Caucasian subjects.

NKIRAS1 and NKIRAS2 (also called as κB-Ras) were identified as members of the atypical RAS family that suppress the transcription factor NF-κB. However, their function in carcinogenesis is still controversial. To clarify how NKIRAS acts on cellular transformation, we generated transgenic mice in which NKIRAS2 was forcibly expressed using a cytokeratin 15 (K15) promoter, which is mainly activated in follicle bulge cells. The ectopic expression of NKIRAS2 was mainly detected in follicle bulges of transgenic mice with NKIRAS2 but not in wild type mice. K15 promoter-driven expression of NKIRAS2 failed to affect the development of epidermis, which was evaluated using the expression of K10, K14, K15 and filaggrin. However, K15 promoter-driven expression of NKIRAS2 effectively suppressed the development of skin tumors induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA). This observation suggested that NKIRAS seemed to function as a tumor suppressor in follicle bulges. However, in the case of oncogenic HRAS-driven cellular transformation of murine fibroblasts, knockdown of NKIRAS2 expression drastically suppressed HRAS-mutant-provoked cellular transformation, suggesting that NKIRAS2 was required for the cellular transformation of murine fibroblasts. Furthermore, moderate enforced expression of NKIRAS2 augmented oncogenic HRAS-provoked cellular transformation, whereas an excess NKIRAS2 expression converted its functional role into a tumor suppressive phenotype, suggesting that NKIRAS seemed to exhibit a biphasic bell-shaped enhancing effect on HRAS-mutant-provoked oncogenic activity. Taken together, the functional role of NKIRAS in carcinogenesis is most likely determined by not only cellular context but also its expression level.

Activation of signal transducer and activator of transcription (STAT)3 has been reported in many cancers. It is also well known that STAT3 is activated in skin lesions of psoriasis, a chronic skin disease. In this study, to ascertain whether patients with psoriasis have a predisposition to STAT3 activation, we examined phosphorylated STAT3 in cancer cells of psoriasis patients via immunohistochemistry. We selected patients with psoriasis who visited the Department of Dermatology, Jichi Medical University Hospital, from January 2000 to May 2015, and had a history of cancer. We performed immunostaining for phosphorylated STAT3 in tumor cells of five, four, and six cases of gastric, lung, and head and neck cancer, respectively. The results showed that there was no significant difference in STAT3 activation in any of the three cancer types between the psoriasis and control groups. Although this study presents limitations in its sample size and inconsistency in the histology and differentiation of the cancers, results suggest that psoriasis patients do not have a predisposition to STAT3 activation. Instead, STAT3 activation is intricately regulated by each disorder or cellular microenvironment in both cancer and psoriasis.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare, inflammatory skin disease characterized by recurrent flares of pustulation accompanied by systemic symptoms that can be life-threatening. The clinical and humanistic burden of GPP in Japan is high, and it is a designated intractable disease. We reviewed clinical evidence and guidelines for GPP treatment in Japan to identify unmet needs and assess data supporting the development and use of new targeted therapies. AREAS COVERED: Using specific search terms in PubMed and Embase, with additional back-referencing, we retrieved literature related to GPP in Japan focusing on clinical and pathogenic characteristics, diagnosis, and treatment. EXPERT OPINION: Although there are approved systemic therapies for GPP in Japan, all present uncertainties in terms of safety and efficacy. Clinical evidence supporting their use comes mostly from studies in patients with mild or moderate disease, and their effectiveness in treating acute phase GPP is unknown. The interleukin-36 pathway appears to be central to GPP pathogenesis. New therapies targeting this pathway show promise in patients presenting with acute phase GPP. The rarity and intermittent course of GPP make it challenging to recruit sufficient patients for trials and robustly investigate the efficacy and safety of these agents to treat GPP.

The production of melanin pigments by melanocytes and their quantity, quality, and distribution play a decisive role in determining human skin, eye, and hair color, and protect the skin from adverse effects of ultraviolet radiation (UVR) and oxidative stress from various environmental pollutants. Melanocytes reside in the basal layer of the interfollicular epidermis and are compensated by melanocyte stem cells in the follicular bulge area. Various stimuli such as eczema, microbial infection, ultraviolet light exposure, mechanical injury, and aging provoke skin inflammation. These acute or chronic inflammatory responses cause inflammatory cytokine production from epidermal keratinocytes as well as dermal fibroblasts and other cells, which in turn stimulate melanocytes, often resulting in skin pigmentation. It is confirmed by some recent studies that several interleukins (ILs) and other inflammatory mediators modulate the proliferation and differentiation of human epidermal melanocytes and also promote or inhibit expression of melanogenesis-related gene expression directly or indirectly, thereby participating in regulation of skin pigmentation. Understanding of mechanisms of skin pigmentation due to inflammation helps to elucidate the relationship between inflammation and skin pigmentation regulation and can guide development of new therapeutic pathways for treating pigmented dermatosis. This review covers the mechanistic aspects of skin pigmentation caused by inflammation.

Skin is the largest and most complex organ in the human body comprised of multiple layers with different types of cells. Different kinds of environmental stressors, for example, ultraviolet radiation (UVR), temperature, air pollutants, smoking, and diet, accelerate skin aging by stimulating inflammatory molecules. Skin aging caused by UVR is characterized by loss of elasticity, fine lines, wrinkles, reduced epidermal and dermal components, increased epidermal permeability, delayed wound healing, and approximately 90% of skin aging. These external factors can cause aging through reactive oxygen species (ROS)-mediated inflammation, as well as aged skin is a source of circulatory inflammatory molecules which accelerate skin aging and cause aging-related diseases. This review article focuses on the inflammatory pathways associated with UVR-mediated skin aging.

BACKGROUND: A wide gender gap exists in many fields in Japan, including the academic society of dermatology. Women are substantially underrepresented in the highest academic ranks. OBJECTIVE: We aimed to clarify the possible factors contributing to the current gender gap in the field of academic dermatology and to recommend necessary measures to decrease the gender gap. METHODS: We performed a cross-sectional study of faculty members' academic productivity at the dermatology departments of all the educational institutions in Japan in 2019. RESULTS: Women had significantly lower academic productivity than men. A significant gender difference in academic productivity was found in lecturers and assistant professors but not in associate professor and professor positions. This gender difference was still significant after normalizing the productivity for career length. CONCLUSION: Our findings suggest the need to encourage women lecturers and assistant professors to improve their academic achievement to decrease the gender gap in academic dermatology.

Psoriasis is a chronic, immune-mediated inflammatory disease that predominantly affects the skin and joints. The recent therapeutic development for psoriasis has been remarkable and biologics have dramatically changed the treatment of psoriasis. In moderate-to-severe cases, systemic therapies are required to control their symptoms and biologics can provide greater efficacy when compared with other types of therapies. The coronavirus disease (COVID-19) pandemic has had a great impact on the lives of many people and has worsened substantially worldwide. During the ongoing COVID-19 pandemic, it still remains unclear whether biologics suppress the immune system and increase the risk of COVID-19. In this review, we have summarized the experience with biologics used for treating psoriasis during the COVID-19 pandemic. Biologics seem to be beneficial to COVID-19 infection. Shared decision-making that is based on updated information is highlighted in the time of COVID-19.

We evaluated the pharmacodynamic effects of apremilast in 69 patients who were included in biomarker subanalyses of a phase 2b study that demonstrated the long-term safety and efficacy of apremilast in Japanese adults with moderate to severe psoriasis. The association between cytokine levels and Psoriasis Area and Severity Index (PASI) improvement was evaluated using linear regression and Spearman's rank correlation coefficient analysis. At baseline, median plasma levels of interleukin (IL)-17A, IL-17F and IL-22 were elevated versus reference values for healthy individuals, whereas tumor necrosis factor-α levels were close to normal. With apremilast 30 mg b.i.d., there were significant associations between percentage change in PASI score and percentage change in IL-17A, IL-17F and IL-22 levels at week 16. Findings demonstrate that the efficacy of apremilast in psoriasis is associated with inhibition of key cytokines involved in the pathology of psoriasis.

OBJECTIVE: To identify the narrowband ultraviolet B (NB-UVB)-induced molecular mechanisms that may account for their anti-inflammatory efficacy, gene expression and transcriptome profiling, which were performed using advanced molecular techniques. METHODS: This research was conducted on patients with moderate-to-severe plaque-type psoriasis who received NB-UVB treatment. RNA sequencing (RNA-Seq) was conducted to assay the transcriptomes and identify the differentially expressed transcripts that had been enriched during the major pathway analysis. RESULTS: Clinical improvement of psoriasis by NB-UVB therapy is linked to the suppression of the "immunological signaling pathways" and "cell cycle regulatory, growth and proliferation pathways" which are critical to the pathogenesis of the disease. In addition, these results were further substantiated by demonstrating that NB-UVB therapy has a significant effect on keratinocyte differentiation and affects the regulation of genes and inflammatory mediators that are related to cell proliferation and apoptosis. Moreover, NB-UVB phototherapy is also involved with the downregulation of toll-like receptors signaling in lesional psoriasis. CONCLUSION: NB-UVB is an effective treatment for psoriasis. Our study supports the conclusion that the clinical effectiveness of NB-UVB therapy is based on the suppression of a broad range of inflammatory signaling pathways, gene expression of inflammatory cytokines and increased expressions of anti-inflammatory signaling pathways in psoriatic skin. This is the first study that applied advanced molecular techniques to investigate phototherapy as a new key to unlock genetic knowledge and create novel information. Ultimately, the goal is to increase medical knowledge and improve the patient care of psoriasis.

Psoriasis is a chronic inflammatory cutaneous disease, characterized by activated plasmacytoid dendritic cells, myeloid dendritic cells, Th17 cells, and hyperproliferating keratinocytes. Recent studies revealed skin-resident cells have pivotal roles in developing psoriatic skin lesions. The balance in effector T cells and regulatory T cells is disturbed, leading Foxp3-positive regulatory T cells to produce proinflammatory IL-17. Not only acquired but also innate immunity is important in psoriasis pathogenesis, especially in triggering the disease. Group 3 innate lymphoid cell are considered one of IL-17-producing cells in psoriasis. Short chain fatty acids produced by gut microbiota stabilize expression of Foxp3 in regulatory T cells, thereby stabilizing their function. The composition of gut microbiota influences the systemic inflammatory status, and associations been shown with diabetes mellitus, cardiovascular diseases, psychomotor diseases, and other systemic inflammatory disorders. Psoriasis has been shown to frequently comorbid with diabetes mellitus, cardiovascular diseases, psychomotor disease and obesity, and recent report suggested the similar abnormality in gut microbiota as the above comorbid diseases. However, the precise mechanism and relation between psoriasis pathogenesis and gut microbiota needs further investigation. This review introduces the recent advances in psoriasis research and tries to provide clues to solve the mysterious relation of psoriasis and gut microbiota.

As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Since 2015, three IL-17 inhibitors of secukinumab and ixekizumab, anti-IL-17A antibodies, and brodalumab, an anti-IL-17 receptor antibody, and two anti-IL-23p19 antibodies of guselkumab and risankizumab, have also been launched. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors and patient background factors, sharing such information with patients. The following can be listed as points to be considered for the selection of biologics: drug effects (e.g. strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g. infections, administration-related reactions and relationships with other comorbidities), convenience for patients (e.g. hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration) and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.

<title>Abstract</title>A lysosomal transmembrane protein SLC29A3 transports nucleosides from lysosomes to the cytoplasm. Loss-of-function mutations of the SLC29A3 gene cause lysosomal nucleoside storage in monocyte/macrophages, leading to their accumulation called histiocytosis in humans and mice. Little is known, however, about a mechanism behind nucleoside-dependent histiocytosis. TLR7, an innate immune sensors for single stranded RNA, bind and respond to nucleosides. We here show that they drive nucleoside-mediated histiocytosis. Patrolling monocyte/macrophages accumulate in the spleen of <italic>Slc29a3</italic>^−/− mice but not <italic>Slc29a3</italic>^−/−<italic>Tlr7</italic>^−/− mice. Accumulated patrolling monocyte/macrophages stored nucleosides derived from cell corpse. TLR7 was recruited to phagosomes and activated as evidenced by TLR7-dependent phagosomal maturation. TLR7 induced hyper-responsiveness to M-CSF in <italic>Slc29a3</italic>^−/− monocyte/macrophages. These results suggest that TLR7 drives histiocytosis in SLC29A3 disorders. <sec><title>One Sentence Summary</title>SLC29A3 disorders are caused by activation of TLR7 with accumulated nucleosides in lysosomes. </sec>

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.